The present disclosure generally relates to biodegradable and bioresorbable materials having a mineral layer on the surface of the material. More particularly, the disclosure relates to biodegradable and bioresorbable orthopedic devices having a degradable mineral layer on the surface thereof that can be used as a delivery vehicle for biological substances. Also provided are various methods of using the mineralized devices in tissue regeneration, including bone tissue engineering, and methods for producing the mineralized devices.
The field of orthopedic tissue engineering has developed rapidly in response to the expanding need for skeletal tissue replacements to treat injury, disease, and birth defects. Costs of musculoskeletal conditions represent an average of 3% of the gross domestic product of developed countries, an estimated $254 billion annually in the United States, and bone and joint diseases account for half of all chronic conditions in people over the age of 50. The predicted doubling of this age group's population by 2020 suggests that the tremendous need for novel bone repair and replacement therapies will continue to grow rapidly. Bone-tendon healing presents a particularly challenging problem that must be addressed in myriad orthopedic applications, including cruciate ligament reconstruction, rotator cuff repair, patellar tendon repair, and avulsion injury repair.
Anterior cruciate ligament (ACL) reconstruction provides an illustrative and well-characterized example of the importance of bone-tendon healing, as there are more than 239,000 cruciate ligament reconstructions performed annually, with a total cost of $3.5 billion. ACL reconstruction surgery generally involves 4 steps: 1) removal of the damaged ligament; 2) drilling of tunnels through the tibia and the femur for graft positioning; 3) placement of a hamstring tendon or patellar tendon graft into these bone tunnels using a suture as a guide; and 4) fixation of the graft with interference screws, which minimize graft motion in the femoral and tibial tunnels.
Although widely successful in enhancing knee stability, the process of cruciate ligament reconstruction is plagued by significant limitations. The first is tunnel widening. Without screw fixation 75% of patients have at least 60% widening of their femoral tunnels 30 months after surgery, and a recent study has shown that even with screw fixation the femoral and tibial tunnel areas increase by 102% and 85% twelve months after surgery. This tunnel widening is indicative of bone resorption instead of the desired tendon-bone healing, and it creates significant reconstructive challenges in the 5-10% of cases that require revision surgery. A second limitation in ACL reconstruction is the extensive amount of time required for full patient recovery, which is typically a 6 month timeframe. Taken together, these limitations cause a significant increase in patient morbidity and loss of physical activity, and these issues are typical in other clinical scenarios that require bone-tendon healing.
It has recently been demonstrated that soluble growth factors may play a role during the various stages of bone tendon healing, including the inflammatory phase, the proliferation phase, and the remodeling phase (Murphy, et al., “Healing of Bone and Connective Tissues,” in Encyclopedia of Biomaterials and Biomedical Engineering, Wnek, G. B., ed., Informa Healthcare, 2006). For instance, a recent study indicated that the growth factors FGF-2, BMP-2, and VEGF are each upregulated during various stages of healing after ACL reconstruction surgery, and that these proteins contribute to functional bone-tendon integration (Kohno, et al., “Immunohistochemical demonstration of growth factors at the tendon-bone interface in anterior cruciate ligament reconstruction using a rabbit model,” J. Orthop. Sci., 2007, Vol. 12(1) p. 67-73). It has also been shown that BMP-2 delivery from a collagen sponge can promote rapid bone formation in a tibial tunnel in a canine model (Rodeo, et al., “Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel,” Am. J. Sports Med., 1999, Vol. 27 (4), p. 476-88), and that tendon grafts soaked in a VEGF solution prior to implantation promote enhanced blood vessel growth into the bone tunnel, thereby increasing graft viability (Yoshikawa, et al., “Effects of local administration of vascular endothelial growth factor on mechanical characteristics of the semitendinosus tendon graft after anterior cruciate ligament reconstruction in sheep,” Am. J. Sports Med., 2006, Vol. 34(12), p. 1918-25). Other proteins, including FGF-2 and α2-macroblobulin, have also shown promise as therapeutic agents to improve ACL reconstruction outcomes.
In view of the prevalence of growth factor signaling during orthopedic tissue healing, including bone-tending healing, strategies have been developed to deliver growth factors to skeletal tissues. Traditional “sustained” growth factor delivery approaches have focused on embedding proteins in plastic microspheres (e.g., poly(lactide-co-glycolide) microspheres) or suspending proteins in hydrogels (e.g., type I collagen gels). The advent of these technologies has had a revolutionary effect on medicine, and the worldwide market for drug delivery technology exceeds $100 billion. However, although these approaches have been useful in a wide variety of biomedical applications, their application to functional bone and tendon healing is pragmatically limited. Plastic microspheres do not represent a stand alone device for tissue ingrowth and are difficult to process into structural orthopedic devices while retaining protein biological activity. Hydrogels are also non-ideal carriers, as growth factors typically transport out of the hydrogel rapidly, resulting in limited, short-term delivery.
Recent approaches have also been developed that allow for longer term growth factor release, e.g., up to several months, within a biodegradable polymer “scaffold” that can support tissue ingrowth, including porous plastic scaffolds and chemically modified hydrogels. Although these previous growth factor delivery approaches have been successful in actively influencing bone regeneration within scaffold materials, pragmatic challenges limit the implementation of growth factor delivery strategies in clinical orthopedics. First, current growth factor delivery platforms release a substantial amount of protein in the first 48 hours of use, a phenomenon known as “burst” release. This rapid “burst” may be particularly problematic in orthopedic surgery applications, in which an acute inflammatory response in the first 3-5 days after surgery floods the local environment with blood-born growth factors that may mask the effects of the protein being delivered. Second, materials that serve as carriers for delivery of bone growth factors are typically unsuitable for clinical orthopedic applications due to their inappropriate geometry and poor bulk mechanical properties.
Bioresorbable devices constitute a significant portion of the orthopedic industry ($100.5 million total market size) and this market is expected to grow dramatically for the foreseeable future. In the cruciate ligament fixation market bioresorbable devices had a 23% market penetration in 2002 ($14.1 million total market), and this penetration is expected to increase substantially in the next 5 years. The most common class of bioresorbable polymer used clinically are the poly(α-hydroxy esters) which include poly(L-lactic acid) (PLLA), poly(lactide-co-glycolide) (PLG), poly(dioxanone) (PDS), and poly(ε-caprolactone (PCL). These polymers are used as nails, pins, anchors, screws, plates, sutures, and scaffolds for a variety of orthopedic applications. Sutures are particularly ubiquitous, and they are a key component of virtually all bone-tendon healing applications in orthopedics. In each case, the unique goal of bioresorbable devices is to serve as temporary fixation devices, with the intent that after tissue healing the host tissues will assume this function. Therefore, proper function of these devices requires new tissue formation in concert with device resorption. However, typical bioresorbable devices do not actively promote new tissue formation, and the processing conditions used to generate these devices typically employ high temperatures and/or organic solvents that preclude incorporation of biologically active proteins (e.g., growth factors) capable of inducing new tissue growth. Therefore, there is a need for new approaches that allow for controlled protein delivery from bioresorbable devices, such as sutures, commonly used in clinical applications.
It has now been discovered that limitations associated with growth factor delivery during orthopedic tissue healing can be addressed by synthesizing a mineral layer, such as a hydroxyapatite (HAP) layer, on standard biodegradable or bioresorbable orthopedic devices, and engineering these layers to deliver growth factors or other biological substances in a spatially and temporally controlled manner.